Infertility in humans is said to be observed around 10% of the couples. Therefore, there have been significant needs for fertility treatment, and by now, it is commonly practiced. Among different current methods of fertility treatment, those in which sperm cells or eggs are directly handled are known as artificial insemination and in vitro fertilization, respectively. Artificial insemination is a technique to promote pregnancy by injecting sperm cells into the vagina at a position close to the cervix, or directly into the uterus or the oviducts, using an instrument such as catheter and the like, and it aims to increase the success rate of fertilization, by artificially conducting a process which then leads sperm cells to meet an egg. On the other hand, in vitro fertilization is a technique by which a patient is administered an ovulation inducer to induce generation of ova, which then are collected out of the body and mixed with sperm cells in a test tube to have them got fertilized, and the fertilized eggs then are cultured and, generally on days 2-3 of culture, embryos at the 4- or 8 cell stage are transferred, generally into the uterine cavity, with a catheter. In order to make the implantation of the transferred embryos easier, administration of luteinizing hormone is usually carried out in order to condition the uterine endometrium.
A preimplantation embryo produces several factors during its development to signal its presence to the maternal organism. Interleukin-1 (IL-1), for example, is a primary factor which modulates cross talks between the embryo and the uterine endometrium of the maternal organism, and the IL-1 system is found at all the stages of development (Non-Patent Literature 1). With regard to human chorionic gonadotropin (hCG), another of the embryonic factors, expression of its gene can be found to occur already in the 2-cell stage embryo (Non-Patent Literature 2). It also is observed that several embryonic factors, including the above two, involved in the cross talks are released out of the cells when an embryo is cultured in vitro (in a test tube). Namely, several embryonic factors that modulate endometrial receptivity are detectable in the supernatant of embryo cultures (Non-Patent Literatures 3-9). It is known that, in vivo also, an embryo developing in the oviduct induces differentiation of the uterine endometrium (Non-Patent Literature 10). All these facts, taken together, indicate that the cross talks take place via the factors produced by the embryo between the embryo and the uterine endometrium, at the early stages of embryonic development. In fact, it has been shown that not only a preimplantation embryo in the uterine cavity, but even an early embryo still remaining in the oviduct has the ability to modulate certain molecules in the uterine endometrium to place its implantation under its own control (Non-Patent Literature 10).
In recent years, blastocyst transfer, which is a technique of in vitro fertilization performed as fertility treatment, has been proposed and practiced clinically as a means of improving the success rate of implantation in human fertility treatment (Non-patent Literatures 11-13). In this technique, embryos produced by in vitro fertilization as described above are cultured for 5 to 6 days to let them develop into blastocysts, which then are injected into the uterine cavity. Employing the technique of blastocyst transfer, higher implantation rates are achieved compared with transferring embryos which are at earlier stages, for the former has such advantages that it allows physiological synchronization of the uterine endometrium with the developmental stage of the embryos, as well as relatively easier selection of embryos with higher ability for implantation owing to a longer in vitro culture (Non-Patent Literatures 14 and 15). Even so, however, the success rate of pregnancy by blastocyst transfer actually remains at a low level of about 36.4%. Unsuccessful implantation after blastocyst transfer is thought to be due, e.g., to failure of the blastocyst to escape from the zona pellucida or to arrested development of the transplanted blastocyst in the uterine cavity. Further, lack of cross talks between the uterine endometrium and the embryo at the development stages from early embryo to blastocyst is thought to be another cause of failure. This lack of exchange of information can be a cause of insufficient modulation of the uterine endometrium's receptivity to embryos.
In order to increase the success rate of pregnancy in blastocyst transfer, a method has been developed in which the supernatant of a culture obtained by culturing a human embryo in a medium until it develops into a blastocyst is injected into the uterine cavity prior to the transfer of a blastocyst into the uterus [SEET (Stimulation of Endometrium Embryo Transfer) therapy]. According to this method, 90% or greater success rate of pregnancy is achieved (Non-Patent Literature 16 and Patent Literature 1). This improvement in the success rate of pregnancy by SEET therapy suggests that the supernatant of the culture which is injected into the uterine cavity contains some active ingredient which can improve success rate of pregnancy. However, it is not known what such active ingredient is.
Though phospholipids generally have two fatty acid moieties, certain phospholipids occuring in the living body have no more than one fatty acid moiety. They are called “lysophospholipids”. Lysophosphatidic acid, one of known lysophospholipids, corresponds to 1-acylglycerol 3-phosphate or 2-acylglycerol 3-phosphate. It is commonly known that various lysophosphatidic acids differing from one another in their fatty acid moieties occur in the living body and that they have physiological activities, such as promotion of cellar growth, for example. Lysophosphatidic acids exert their activities mainly through cell surface receptors, of which at least 4 types are known (LPA1, LPA2, LPA3, and LPA4). Though a study on mice lacking the gene of one of these lysophosphatidic acid receptors, LPA3, has shown that signal transduction via LPA3 plays an important role in implantation of a fertilized egg (Non-Patent Literature 17), it is not known which of the phosphatidic acids involved.